The MiR-135b–BMAL1–YY1 loop disturbs pancreatic clockwork to promote tumourigenesis and chemoresistance

• DOI: 10.1038/s41419-017-0233-y
• Publication Date: 2018-02-02T13:15:40Z
• Authors: Weiliang Jiang; Senlin Zhao; Jia Shen; Lihong Guo; Yi Sun; Yuntian Zhu; Zhixiong Ma; Xin Zhang; Yangyang Hu; Wenqin Xiao; Kai Li; Sisi Li; Li Zhou; Li Huang; Zhanjun Lu; Yun Feng; Junhua Xiao; Eric Erquan Zhang; Lijuan Yang; Rong Wan
• Keywords: Feedback, Physiological; Male; 0301 basic medicine; 2. Zero hunger; Mice, Inbred BALB C; 0303 health sciences; Carcinogenesis; Pancreatic Ducts; ARNTL Transcription Factors; Mice, Nude; Epithelial Cells; Prognosis; Article; Gene Expression Regulation, Neoplastic; Pancreatic Neoplasms; MicroRNAs; 03 medical and health sciences; Biological Clocks; Cell Movement; Drug Resistance, Neoplasm; Cell Line, Tumor; Animals; Humans; Neoplasm Invasiveness; Cell Proliferation

AbstractCircadian disruption has been implicated in tumour development, but the underlying mechanism remains unclear. Here, we show that the molecular clockwork within malignant human pancreatic epithelium is disrupted and that this disruption is mediated by miR-135b-induced BMAL1 repression. miR-135b directly targets the BMAL1 3′-UTR and thereby disturbs the pancreatic oscillator, and the downregulation of miR-135b is essential for the realignment of the cellular clock. Asynchrony between miR-135b and BMAL1 expression impairs the local circadian gating control of tumour suppression and significantly promotes tumourigenesis and resistance to gemcitabine in pancreatic cancer (PC) cells, as demonstrated by bioinformatics analyses of public PC data sets and in vitro and in vivo functional studies. Moreover, we found that YY1 transcriptionally activated miR-135b and formed a ‘miR-135b–BMAL1–YY1’ loop, which holds significant predictive and prognostic value for patients with PC. Thus, our work has identified a novel signalling loop that mediates pancreatic clock disruption as an important mechanism of PC progression and chemoresistance.